Skin Cancer & Melanoma

Melanoma continues to be a poorly understood and frequently under-recognized cancer threat to society. The authors have provided a comprehensive overview of this malignancy from diagnosis to advanced-stage therapy.

Melanoma affects persons of all ages, causing more years of lost life than any other cancer except leukemia.[1] The American Cancer Society estimates that about 68,720 new melanomas will be diagnosed in the US in 2009, with more than 8,650 deaths, and an estimated lifetime risk of 1 in 50 for whites, 1 in 200 for Hispanics, and 1 in 1,000 for blacks.[2]

Synta and GlaxoSmithKline will end their agreement to develop and market elesclomol for the treatment of metastatic melanoma after lackluster results from the SYMMETRY trial.

Preliminary findings from a phase III, multicenter trial show that adding a novel cancer vaccine-called gp100:209-217(210M) peptide-to standard therapy doubles response rates and extends progression-free survival in patients with metastatic melanoma, without causing significant side effects (abstract CRA9011).

PHOENIX, Ariz.-In patients with intermediate thickness localized melanoma, wide excision surgery is usually curative, but metastasis to regional lymph nodes can occur. Some clinicians advocate immediate elective lymphadenectomy in these patients who have positive sentinel node biopsies as a way to improve tumor staging and survival.

Annually, about 8,000 patients are found to have metastatic melanoma presenting as recurrence of an earlier primary melanoma, and this number closely approximates the annual number of deaths from the disease. This statistic illustrates the lack of progress that has been made in the treatment of stage IV melanoma over the past several decades.

Reviewing treatment modalities for melanoma provides many sobering reminders that advances in our scientific understanding have not yet translated into meaningful clinical benefit. As clearly delineated by the authors, the “standard” treatment of dacarbazine chemotherapy has a poor response rate and lacks durability.

The article by Bhatia and colleagues focuses on the treatment of patients with metastatic melanoma using standard therapies, but it also includes a brief outline of recent treatment approaches using investigational agents. In addition, the authors describe prognostic factors for metastatic melanoma, highlighting the impact of the extent of tumor and the site of metastasis (eg, soft-tissue vs visceral metastases) on survival.

Metastatic melanoma continues to be a challenging disease to treat, with an estimated 8,420 related deaths in the United States in 2008.[1] The 10- year survival rate for patients with metastatic melanoma is less than 10%.[2] More than 3 decades after its initial approval by the US Food and Drug Administration (FDA) in 1975, dacarbazine continues to be the standard of care for most patients with this disease. High-dose interleukin-2 (HD IL-2 [Proleukin]), approved by the FDA in 1998 for metastatic melanoma, benefits a small subset of patients.

The recommendation to minimize sun exposure to prevent skin cancer has produced a pandemic of vitamin D deficiency. Vitamin D has generated considerable interest in the past decade, as accumulating evidence from both retrospective and prospective epidemiologic studies suggests an association between vitamin D deficiency and increased risk of autoimmune, infectious, and cardiovascular diseases, as well as cancer.

It is estimated that more than 62,000 men and women will be diagnosed with melanoma in 2008, with more than 8,400 deaths, and an estimated lifetime risk predicted to be 1 in 55.[1] Although deadly in its later stages, melanoma carries an excellent prognosis if it is diagnosed early. Fortunately, most melanoma cases (80%) are diagnosed at a localized stage; the 5-year survival rate for this group is 98.5%.

Melanoma frequently metastasizes to the small bowel. In this installment of Clinical Quandaries, we describe the case of 74-year-old man who presented with this rare but well described manifestation of malignant melanoma

Small bowel metastases from melanoma are uncommon. While the authors reference two studies that reported a large proportion of patients with small bowel metastases, the true incidence of gastrointestinal (GI) lesions in melanoma patients is much lower.

The University of Colorado Health Sciences Center holds weekly second opinion conferences focusing on cancer cases that represent most major cancer sites. Patients seen for second opinions are evaluated by an oncologist.

STOCKHOLM-Elesclomol, an investigational small-molecule oxidative stress inducer (Synta Pharmaceuticals), in combination with paclitaxel (Taxol) showed a trend toward improved survival in stage IV metastatic melanoma patients, compared with paclitaxel alone.

During this election year, approximately 1.4 million U.S. residents will be diagnosed with cancer. For U.S. presidential hopefuls Sen. Barack Obama and Sen. John McCain, cancer has hit close to home. Sen. McCain, 72, has been treated several times for squamous cell carcinoma and malignant melanoma. Sen. Obama lost his grandfather to prostate cancer and his mother to ovarian cancer.

The natural history of melanoma has changed little over the years, despite advances in testing and treatment such as cytotoxics, DNA-damaging agents, antimicrotubule drugs, and immunomodulatory therapies. Only 15% of advanced-stage patients respond to the two FDA-approved agents, interleukin-2 and dacarbazine (DTIC or DTIC-Dome).

Radiation therapy (RT) and immunotherapy of cancer both date back more than 100 years, and yet, because radiation was often considered immunosuppressive, there had been little enthusiasm for combining them until recently. Immunotherapy has an established role in the treatment of some cancers-superficial bladder cancer treated with bacillus Calmette-Guérin (BCG), renal cell carcinoma and melanoma treated with interferon and interluekin (IL)-2 (Proleukin), and breast cancer and lymphoma treated with monoclonal antibodies such as trastuzumab (Herceptin) and rituximab (Rituxan), which partly function through antibody-dependent cellular cytotoxicity.

Results from an adjuvant trial in high-risk melanoma patients demonstrated that a majority of patients treated with granulocyte-macrophage colony-stimulating factor, or sargramostim (Leukine), achieved disease-free and/or overall survival.

Along with various imaging modalities, serologic tumor markers such as CA 15-3 and CA 27.29 have been used for decades to monitor treatment response in patients with metastatic breast cancer (MBC). Despite the frequent use of these markers, they lack high sensitivity and specificity for breast cancer progression. The prognostic significance of these markers remains indeterminate because of the conflicting outcome of many clinical trials. The circulating tumor cell (CTC) test has recently been studied in clinical trials in patients with MBC. Some of the studies showed that high levels of CTCs are correlated with poor survival in MBC. An intergroup trial is underway to determine the implication of changing treatment based on the CTC level. This article will discuss the current data on these markers, with special emphasis on the CTC test. The potential clinical utility of these markers will also be discussed.

Bone metastases are a common feature of many solid cancers, especially those originating from the prostate, breast, lung, kidney, melanoma, and other sites. Up to 80% of patients with these cancers will develop painful bony disease during the course of their disease.

Pfizer Inc has discontinued a phase III trial of single-agent tremelimumab in patients with advanced melanoma after the review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy.

University of Pittsburgh Cancer Institute researchers have discovered a previously unknown virus strongly associated with Merkel cell carcinoma, a rare but aggressive skin cancer that typically affects elderly and immunosuppressed individuals

In a surprising discovery, reported at RSNA 2007, researchers from Germany have found that whole-body staging of patients with recently diagnosed malignant melanoma using either MRI or PET/CT could miss a substantial number of metastatic lesions

Schering-Plough Corporation has announced that FDA has granted priority review to its supplemental Biologics License Application for Pegintron (pegylated interferon alfa-2b) as adjuvant therapy for patients with stage III melanoma.

US Food and Drug Administration (FDA) has accepted the peginterferon alfa-2b (PEG-Intron) supplemental Biologics License Application (sBLA) for for review and has granted Priority Review status to the drug for the adjuvant treatment of patients with stage III melanoma

A new type of agent, an oxidative stress inducer, combined with paclitaxel improved survival in patients with metastatic melanoma, compared with paclitaxel alone

GSK and Synta announce STA-4783 collaboration

Integrins have direct effects in stimulating proliferation and preventing apoptosis in cancer cells and mediating proangiogenic interactions between endothelial cells and extracellular matrix. Alterations of expression of various integrins and their receptors have been observed in various cancers in which angiogenesis is known to play a role, including colorectal cancer. Inhibition of specific integrins might thus inhibit both direct effects of integrins on cancer cells and tumor angiogenesis. Inhibitory peptides and anti-integrin monoclonal antibodies are currently being investigated in clinical trials in patients with solid tumors, with early evidence suggesting clinical benefit in disease stabilization with use of an anti-αvβ3 antibody in the settings of colorectal cancer, renal cell carcinoma, and melanoma. Integrin inhibition alone and with other targeted therapeutic approaches should be further investigated in clinical trials in patients with colorectal cancer.

Integrins play an important physiologic role in cell adhesion, and accumulating evidence suggests that they also regulate cell growth, proliferation, migration, and apoptosis. A number of congenital and acquired disease states have been associated with integrins, and small- molecule integrin inhibitors have been approved for treatment of benign hematologic diseases. In cancer, aberrant expression with normal functioning rather than dominant genetic variations of genes coding for integrins has generally been observed. This aberrant expression is mediated through "bidirectional" receptor signaling and interaction with corresponding signals from growth factor signaling pathways, leading to inhibition of apoptosis, induction of cell proliferation, extracellular matrix remodeling, migration, and angiogenesis. From a clinical perspective, a growing number of molecules targeting integrins have been developed for treatment and imaging purposes; clinical studies in melanoma, prostate cancer, and other malignancies are underway. This review summarizes the biology of integrins, the signal transduction pathways they regulate, and their role in different stages of carcinogenesis. Furthermore, it provides a synopsis on the clinical advancements in integrin targeting for therapeutic and imaging purposes in cancer.